tbuckley/cabot-search huggingface dataset:
Exploring disease comorbidities and temporal disease progression of psoriasis: an observational, retrospective, multi-database, cohort study
Authors: Nana A L Rosenø, Erik Hillo Lørup, Craig Richardson, Ivette Alarcon, Alexander  Egeberg
Journal: British Journal of Dermatology (2022)

Abstract Background Comorbidities associated with psoriasis are well documented. However, few studies have explored the comorbidity trajectories that patients with psoriasis commonly experience over time. This study reports the 5-year comorbidity trajectories of patients with psoriasis. Objectives To determine the long-term comorbidity trajectories of patients with psoriasis in Denmark. Methods This observational cohort study explored the Danish National Patient Registry (DNPR) between 1999 and 2013 to identify comorbidities diagnosed 5 years prior to or after a psoriasis diagnosis. Comorbidity occurrence in patients with psoriasis (psoriasis cohort) was compared with patients without psoriasis (the N group). Comparison groups, each the same size as the psoriasis cohort, were created by selecting random patients from the N group. If a comorbidity occurrence was higher in more than nine comparison groups than in the psoriasis cohort, it was not analysed and only comorbidities that occurred in ≥ 0·8% of the psoriasis cohort were analysed. The strength of association between a psoriasis diagnosis and a comorbidity diagnosis was measured using relative risk (RR). All psoriasis and comorbidity pairs that achieved RR &amp;gt; 1 (P &amp;lt; 0·001) (known as a Diagnosed Pair) were tested for directionality to identify the sequence of diagnoses using a binomial test. Diagnosed Pairs with a statistically significant direction (Bonferroni corrected P-value &amp;lt; 0·025) were then used to create comorbidity trajectory clusters 5 years before and after a psoriasis diagnosis. Results A total of 17 683 patients with psoriasis were compared with 10 000 comparison groups. A total of 121 comorbidities met the minimum criteria that ≥ 0·8% of the psoriasis cohort were diagnosed with the comorbidity within 5 years (before or after) of their psoriasis diagnosis. Thirty-eight of these comorbidities achieved RR &amp;gt; 1 (P &amp;lt; 0·001) with psoriasis, of which 19 achieved a significant direction from psoriasis to a comorbidity (including psoriasis to hypothyroidism), and four achieved a significant direction from a comorbidity diagnosis to a psoriasis diagnosis (including Crohn disease to psoriasis); four of five comorbidity trajectories with three sequential diagnoses achieved an RR &amp;gt; 1 (P &amp;lt; 0·001) and a significant direction from psoriasis to the first comorbidity to the second comorbidity (including psoriasis to hypertension to atrial fibrillation and flutter). Conclusions Comorbidity trajectories may support clinicians in conducting disease risk analyses of patients with psoriasis and help plan optimal treatment to prevent future high-risk comorbidities.
A 3D multi-cellular tissue model of the human omentum to study the formation of ovarian cancer metastasis
Authors: Manuela Estermann, Ricardo Coelho, Francis Jacob, Yen-Lin Huang, Ching-Yeu Liang, Ana Bela Faia-Torres, Dedy Septiadi, Barbara Drasler, Bedia Begum Karakocak, Irini Magdelina Dijkhoff, Alke Petri-Fink, Viola Heinzelmann-Schwarz, Barbara Rothen-Rutishauser
Journal: Biomaterials (2023)

Reliable and predictive experimental models are urgently needed to study metastatic mechanisms of ovarian cancer cells in the omentum. Although models for ovarian cancer cell adhesion and invasion were previously investigated, the lack of certain omental cell types, which influence the metastatic behavior of cancer cells, limits the application of these tissue models. Here, we describe a 3D multi-cellular human omentum tissue model, which considers the spatial arrangement of five omental cell types. Reproducible tissue models were fabricated combining permeable cell culture inserts and bioprinting technology to mimic metastatic processes of immortalized and patient-derived ovarian cancer cells. The implementation of an endothelial barrier further allowed studying the interaction between cancer and endothelial cells during hematogenous dissemination and the impact of chemotherapeutic drugs. This proof-of-concept study may serve as a platform for patient-specific investigations in personalized oncology in the future.
Oseltamivir is protective for in-patient mortality in PCR confirmed influenza B and influenza A(H3N2) infections in an historic cohort of 1,048 patients hospitalised during the 2016-17 and 2017-18 influenza seasons
Authors: Mark Reacher, Ben Warne, Neville Q Verlander, Ashley Popay, Lucy Reeve, Nicholas K Jones, Kyriaki Ranellou, Nyaradzai Sithole, Rory Carpenter, Angharad Everden, Elizabeth Jarman, Ali Khalid, Kyle Lam, Chloe Myers, Shuhui Ren, Kathryn J Rolfe, Tommy Sutton, Silvana Christou, Callum Wright, Saher Choudhry, Maria Zambon, Clare Sander, Hongyi Zhang, Hamid Jalal
Journal: Journal of Infection (2023)
Modulation of the gut microbiota engages antigen cross-presentation to enhance antitumor effects of CAR T cell immunotherapy
Authors: Mireia Uribe-Herranz, Silvia Beghi, Marco Ruella, Kalpana Parvathaneni, Silvano Salaris, Nektarios Kostopoulos, Subin S. George, Stefano Pierini, Elisavet Krimitza, Francesca Costabile, Guido Ghilardi, Kimberly V. Amelsberg, Yong Gu Lee, Raymone Pajarillo, Caroline Markmann, Bevin McGettigan-Croce, Divyansh Agarwal, Noelle Frey, Simon F. Lacey, John Scholler, Khatuna Gabunia, Gary Wu, Elise Chong, David L. Porter, Carl H. June, Stephen J. Schuster, Vijay Bhoj, Andrea Facciabene
Journal: Molecular Therapy (2023)

Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types. Several studies have shown the influence of commensal microbes on T cell function, specifically in the setting of checkpoint immunotherapy for cancer. In this study, we investigated how vancomycin-induced gut microbiota dysbiosis affects chimeric antigen receptor (CAR) T immunotherapy using multiple preclinical models as well as clinical correlates. In two murine tumor models, hematopoietic CD19+-A20 lymphoma and CD19+-B16 melanoma, mice receiving vancomycin in combination with CD19-directed CAR T cell (CART-19) therapy displayed increased tumor control and tumor-associated antigens (TAAs) cross-presentation compared with CART-19 alone. Fecal microbiota transplant from human healthy donors to pre-conditioned mice recapitulated the results obtained in naive gut microbiota mice. Last, B cell acute lymphoblastic leukemia patients treated with CART-19 and exposed to oral vancomycin showed higher CART-19 peak expansion compared with unexposed patients. These results substantiate the role of the gut microbiota on CAR T cell therapy and suggest that modulation of the gut microbiota using vancomycin may improve outcomes after CAR T cell therapy across tumor types.
Transcriptional reprogramming restores UBE3A brain-wide and rescues behavioral phenotypes in an Angelman syndrome mouse model
Authors: Henriette O’Geen, Ulrika Beitnere, Miranda S. Garcia, Anna Adhikari, David L. Cameron, Timothy A. Fenton, Nycole A. Copping, Peter Deng, Samantha Lock, Julian A.N.M. Halmai, Isaac J. Villegas, Jiajian Liu, Danhui Wang, Kyle D. Fink, Jill L. Silverman, David J. Segal
Journal: Molecular Therapy (2023)

Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted in brain neurons. Clinical features of AS are primarily due to the loss of maternally expressed UBE3A in the brain. A healthy copy of paternal UBE3A is present in the brain but is silenced by a long non-coding antisense transcript (UBE3A-ATS). Here, we demonstrate that an artificial transcription factor (ATF-S1K) can silence Ube3a-ATS in an adult mouse model of Angelman syndrome (AS) and restore endogenous physiological expression of paternal Ube3a. A single injection of adeno-associated virus (AAV) expressing ATF-S1K (AAV-S1K) into the tail vein enabled whole-brain transduction and restored UBE3A protein in neurons to ∼25% of wild-type protein. The ATF-S1K treatment was highly specific to the target site with no detectable inflammatory response 5 weeks after AAV-S1K administration. AAV-S1K treatment of AS mice showed behavioral rescue in exploratory locomotion, a task involving gross and fine motor abilities, similar to low ambulation and velocity in AS patients. The specificity and tolerability of a single injection of AAV-S1K therapy for AS demonstrate the use of ATFs as a promising translational approach for AS. Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted in brain neurons. Clinical features of AS are primarily due to the loss of maternally expressed UBE3A in the brain. A healthy copy of paternal UBE3A is present in the brain but is silenced by a long non-coding antisense transcript (UBE3A-ATS). Here, we demonstrate that an artificial transcription factor (ATF-S1K) can silence Ube3a-ATS in an adult mouse model of Angelman syndrome (AS) and restore endogenous physiological expression of paternal Ube3a. A single injection of adeno-associated virus (AAV) expressing ATF-S1K (AAV-S1K) into the tail vein enabled whole-brain transduction and restored UBE3A protein in neurons to ∼25% of wild-type protein. The ATF-S1K treatment was highly specific to the target site with no detectable inflammatory response 5 weeks after AAV-S1K administration. AAV-S1K treatment of AS mice showed behavioral rescue in exploratory locomotion, a task involving gross and fine motor abilities, similar to low ambulation and velocity in AS patients. The specificity and tolerability of a single injection of AAV-S1K therapy for AS demonstrate the use of ATFs as a promising translational approach for AS.
Blood immune cells from people with HIV on antiviral regimens that contain tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) have differential metabolic signatures
Authors: Eleni Ritou, Sandro Satta, Anton Petcherski, Maria Daskou, Madhav Sharma, Hariclea Vasilopoulos, Eisuke Murakami, Orian S Shirihai, Theodoros Kelesidis
Journal: Metabolism (2023)
KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer
Authors: Hong Qiu, Vladimir Makarov, Jennifer K. Bolzenius, Angela Halstead, Yvonne Parker, Allen Wang, Gopakumar V. Iyer, Hannah Wise, Daniel Kim, Varna Thayaparan, Daniel J. Lindner, Georges-Pascal Haber, Angela H. Ting, Bing Ren, Timothy A. Chan, Vivek Arora, David B. Solit, Byron H. Lee
Journal: Cancer Research (2023)

Abstract Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability. Significance: A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies.
A four minute guide to the rudiments of health and healthcare for those responsible for maintaining health systems
Authors: Richard Smith
Journal: BMJ (2023)

A four minute guide to the rudiments of health and healthcare for those responsible for maintaining health systems Richard Smith chairHealth and healthcare are different things Conversations about health quickly turn into conversations about healthcare, but healthcare is concerned mostly with sickness.Health is not a product of health systems. Healthcare accounts for only 10% of healthHealth is hard, probably impossible, to define, but by any definition healthcare accounts for only around 10% of health.The health of people is determined by other factors-their life circumstances, environment, genes, and lifestyle, all of which are intermingled. Increasing funding of healthcare paradoxically worsens healthSpending more on healthcare crowds out funding on benefits, pensions, education, housing, public transport, urban redesign, the arts, sports, and other activities that are more important for health than healthcare.This sets up a vicious circle where poorer health means more sickness that the health system must help treat.
Prior Immunization to an Intracellular Antigen Enhances Subsequent Red Blood Cell Alloimmunization in Mice
Authors: Ryan Philip Jajosky, Seema R Patel, Shang-Chuen Wu, Kashyap R Patel, Mischa Li Covington, Mary L Vallecillo-Zúniga, Diyoly Ayona, Ashley Bennett, Chance John Luckey, Krystalyn E Hudson, Jeanne Elise Hendrickson, Stepahanie C Eisenbarth, Cassandra D. Josephson, Patricia E Zerra, Sean R Stowell, Connie M Arthur
Journal: Blood (2023)

Antibodies to red blood cell (RBC) alloantigens can increase morbidity and mortality in transfusion recipients. However, alloimmunization rates can vary dramatically, with some patients never generating alloantibodies following transfusion, while others not only become alloimmunized, but may be prone to generating additional alloantibodies following subsequent transfusion. Previous studies suggest that CD4 T cell responses that drive alloantibody formation recognize the same alloantigen engaged by B cells. However, as RBCs express numerous antigens, both internally and externally, it is possible that CD4 T cell responses directed against intracellular antigens may facilitate subsequent alloimmunization to a surface RBC antigen. Here we show that B cells can acquire intracellular antigens from RBCs. Using a mouse model of donor RBCs expressing two distinct alloantigens, we demonstrate that immune priming to an intracellular antigen, which would not be detected by any currently used RBC compatibility assays, can directly influence alloantibody formation following exposure to a subsequent distinct surface RBC alloantigen. These findings suggest a previously under-appreciated mechanism whereby transfusion recipient responders may exhibit an increased rate of alloimmunization due to prior immune priming toward intracellular antigens.
Collagens in Cancer: Structural Regulators and Guardians of Cancer Progression
Authors: Daniela De Martino, Jose Javier Bravo-Cordero
Journal: Cancer Research (2023)

Abstract Collagen is one of the most abundant proteins in animals and a major component of the extracellular matrix (ECM) in tissues. Besides playing a role as a structural building block of tissues, collagens can modulate the behavior of cells, and their deregulation can promote diseases such as cancer. In tumors, collagens and many other ECM molecules are mainly produced by fibroblasts, and recent evidence points toward a role of tumor-derived collagens in tumor progression and metastasis. In this review, we focus on the newly discovered functions of collagens in cancer. Novel findings have revealed the role of collagens in tumor dormancy and immune evasion, as well as their interplay with cancer cell metabolism. Collagens could serve as prognostic markers for patients with cancer, and therapeutic strategies targeting the collagen ECM have the potential to prevent tumor progression and metastasis.
Designer co-beta-peptide copolymer selectively targets resistant and biofilm Gram-negative bacteria
Authors: Zhangyong Si, Jianguo Li, Lin Ruan, Sheethal Reghu, Ying Jie Ooi, Peng Li, Yabin Zhu, Paula T. Hammond, Chandra S. Verma, Guillermo C. Bazan, Kevin Pethe, Mary B. Chan-Park
Journal: Biomaterials (2023)
A Phase Ib/II Trial of Combined BRAF and EGFR Inhibition in<i>BRAF</i>V600E Positive Metastatic Colorectal Cancer and Other Cancers: The EVICT (Erlotinib and Vemurafenib In Combination Trial) Study
Authors: Lavinia Tan, Ben Tran, Jeanne Tie, Ben Markman, Sumi Ananda, Niall C. Tebbutt, Michael Michael, Emma Link, Stephen Q. Wong, Sushma Chandrashekar, Jerick Guinto, David Ritchie, Rachel Koldej, Benjamin J. Solomon, Grant A. McArthur, Rodney J. Hicks, Peter Gibbs, Sarah-Jane Dawson, Jayesh Desai
Journal: Clinical Cancer Research (2023)

BRAF V600E mutant metastatic colorectal cancer represents a significant clinical problem, with combination approaches being developed clinically with oral BRAF inhibitors combined with EGFR-targeting antibodies. While compelling preclinical data have highlighted the effectiveness of combination therapy with vemurafenib and small-molecule EGFR inhibitors, gefitinib or erlotinib, in colorectal cancer, this therapeutic strategy has not been investigated in clinical studies.We conducted a phase Ib/II dose-escalation/expansion trial investigating the safety/efficacy of the BRAF inhibitor vemurafenib and EGFR inhibitor erlotinib.Thirty-two patients with BRAF V600E positive metastatic colorectal cancer (mCRC) and 7 patients with other cancers were enrolled. No dose-limiting toxicities were observed in escalation, with vemurafenib 960 mg twice daily with erlotinib 150 mg daily selected as the recommended phase II dose. Among 31 evaluable patients with mCRC and 7 with other cancers, overall response rates were 32% [10/31, 16% (5/31) confirmed] and 43% (3/7), respectively, with clinical benefit rates of 65% and 100%. Early ctDNA dynamics were predictive of treatment efficacy, and serial ctDNA monitoring revealed distinct patterns of convergent genomic evolution associated with acquired treatment resistance, with frequent emergence of MAPK pathway alterations, including polyclonal KRAS, NRAS, and MAP2K1 mutations, and MET amplification.The Erlotinib and Vemurafenib In Combination Trial study demonstrated a safe and novel combination of two oral inhibitors targeting BRAF and EGFR. The dynamic assessment of serial ctDNA was a useful measure of underlying genomic changes in response to this combination and in understanding potential mechanisms of resistance.
Research Silos in Cancer Disparities: Obstacles to Improving Clinical Outcomes for Underserved Patient Populations
Authors: Angelique Richardson, Burcu Darst, Genevieve Wojcik, Nikhil Wagle, Svasti Haricharan
Journal: Clinical Cancer Research (2023)

Abstract Despite much vaunted progress in cancer therapeutics and diagnostics, outcomes for many groups of non-White patients with cancer remain worse than those for their White compatriots. One reason for this is the lack of inclusion and representation of non-White patients in clinical trials, preclinical datasets, and among researchers, a shortfall that is gaining wide recognition within the cancer research community and the lay public. Several reviews and editorials have commented on the negative impacts of the status quo on progress in cancer research toward medical breakthroughs that help all communities and not just White patients with cancer. In this perspective, we describe the existence of research silos focused either on the impact of socioeconomic factors proceeding from systemic racism on cancer outcomes, or on genetic ancestry as it affects the molecular biology of cancer developing in specific patient populations. While both these research areas are critical for progress toward precision medicine equity, breaking down these silos will help us gain an integrated understanding of how race and racism impact cancer development, progression, and patient outcomes. Bringing this comprehensive approach to cancer disparities research will undoubtedly improve our overall understanding of how stress and environmental factors affect the molecular biology of cancer, which will lead to the development of new diagnostics and therapeutics that are applicable across cancer patient demographics.
Elevated transferrin receptor impairs T cell metabolism and function in systemic lupus erythematosus
Authors: Kelsey Voss, Allison E. Sewell, Evan S. Krystofiak, Katherine N. Gibson-Corley, Arissa C. Young, Jacob H. Basham, Ayaka Sugiura, Emily N. Arner, William N. Beavers, Dillon E. Kunkle, Megan E. Dickson, Gabriel A. Needle, Eric P. Skaar, W. Kimryn Rathmell, Michelle J. Ormseth, Amy S. Major, Jeffrey C. Rathmell
Journal: Science Immunology (2023)

T cells in systemic lupus erythematosus (SLE) exhibit multiple metabolic abnormalities. Excess iron can impair mitochondria and may contribute to SLE. To gain insights into this potential role of iron in SLE, we performed a CRISPR screen of iron handling genes on T cells. Transferrin receptor (CD71) was identified as differentially critical for T H 1 and inhibitory for induced regulatory T cells (iT regs ). Activated T cells induced CD71 and iron uptake, which was exaggerated in SLE-prone T cells. Cell surface CD71 was enhanced in SLE-prone T cells by increased endosomal recycling. Blocking CD71 reduced intracellular iron and mTORC1 signaling, which inhibited T H 1 and T H 17 cells yet enhanced iT regs . In vivo treatment reduced kidney pathology and increased CD4 T cell production of IL-10 in SLE-prone mice. Disease severity correlated with CD71 expression on T H 17 cells from patients with SLE, and blocking CD71 in vitro enhanced IL-10 secretion. T cell iron uptake via CD71 thus contributes to T cell dysfunction and can be targeted to limit SLE-associated pathology.